Cyclo-addition reactions of aminoacetylenes



United States Patent 3,449,351 CYCLO-ADDITION REACTIONS OF AMINOACETYLENES Heinz G. Viehe, Linkebeek, Belgium, assignor to Union Carbide Corporation, a corporation of New York No Drawing. Continuation-impart of application Ser. No.

376,253, June 18, 1964. This application June 15, 1965,

Ser. No. 464,232

Int. Cl. C07d 55/02, 29/00 US. Cl. 260-308 5 Claims ABSTRACT OF THE DISCLOSURE Aminoacetylenes are reacted with compounds containing non-aromatic unsaturated sites to produce cyclic organic compounds. Examples include the reaction of azides with aminoacetylenes to produce aminotriazoles, the reaction of nitrile oxides with aminoacetylenes to produce amino-oxazoles, and the reaction of imines (Schiif bases) with aminoacetylenes to produce amidines (through a cyclic intermediate). The compounds produced by the process of the invention are useful as hydrogen halide acceptors.

and (b) the reaction of phenylnitrile-N-oxide C H CN O with the same aminoacetylene to give 3 CuH5 The term non-aromatic unsaturated site, as used herein, includes carbon-carbon unsaturation such as double bonds, triple bonds and conjugated double and/or triple bonds, as Well as unsaturation involving atoms other than carbon, such as carbonyl groups C=O), Schifi" bases C=N-), nitrile-N-oxides (CN O), azides (-N=NEN), and the like.

The term cycle-addition reaction, as used herein, means the reaction of one or molecules of an aminoacetylene with one or more molecules of a compound containing at least one non-aromatic unsaturated site to produce a molecule of an organic compound which contains a ring of at least four members, the ring comprising (a) both (originally) acetylenic carbon atoms from each aminoacetylene molecule involved in the reaction and (b) at least two atoms which were part of a non-aromatic unsaturated site from each other (than aminoacetylene) molecule involved in the reaction. The molecular Weight of the cyclic product is exactly the sum of the molecular weights of the reactant molecules.

According to the process of this invention, an aminoacetylene compound and a compound containing at least one non-aromatic unsaturated site are mixed together and malntained at a temperature sufliciently elevated to cause the reaction of the non-aromatic unsaturated site with the triple bond of the aminoacetylene to produce a cyclic compound containing a ring system of at least four members and derived from the acetylenic carbon atoms of the aminoacetylene and at least two atoms which prior to reaction were part of the non-aromatic unsaturated site. Following this initial cycloaddition reaction, the cyclic aminoacetylene derivative may or may not undergo further rearrangement.

The aminoacetylene compounds useful in the process of this invention are those represented by the formula wherein R is a monovalent hydrocarbon group, Y is an R group, a hydrogen atom or an NR group, and two R groups on the same nitrogen atom can together form a divalent alkylene group.

In the compounds of Formula A the various R groups can be the same or diflFerent throughout the same molecule, and the R groups preferably contain from 1 to about 18 carbon atoms.

The R groups in Formula A can be alkyl, aryl, alkaryl, aralkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and the like groups. For example, R canbe methyl, ethyl, n-butyl, tertiary-butyl, 2,2-dimethyl-n-propyl, iso-octyl, octadecyl, phenyl, phenylethyl, terphenyl, cumyl, mesityl, cyclopentyl, ethylcyclohexenyl, allyl, or butyne-Z-yl groups, and the like, and two R groups on the same nitrogen atom can together be tetramethylene, S-ethylhexamethylene, decamethylene, and the like.

Throughout the present specification and claims, C H C H C H C H i-C H and t-C H represent respectively the ethyl, phenyl, phenylene, normal butyl, isobutyl and tertiary butyl groups.

Typical compounds represented by Formula A are-the following:

HCECN(CH3)2 NCECN CHQCHZ C5H5 The compounds of Formula A can be prepared by the reaction of compounds represented by the following formulas CHZCHZCHS F CH-Cfi X X with compounds represented by one of the formulas In Formulas ii, iii, iv, v, vi and vii, R has the meaning defined hereinabove with reference to Formula A, R represents hydrogen or an R group, X represents a halogen, preferably fluorine, chlorine, or bromine, and M represents an alkali metal, namely, lithium potassium, rubidium,cesium or francium.

The process for producing the compounds of Formula A comprises mixing together in a hydrocarbon, hydrocarbon ether ortertiary amine solvent a compound of Formula ii, iii, iv or v and a compound of Formula vi or vii, and maintaining the mixture at a temperature between about 25 C. and 150 C. until the compound of Formula A is produced. Preferably, the reactants are employed in the ratio of at least one mole of the compound of Formula vi or vii per gram atom of halogen in the compound of Formula ii, iii, iv, or v. A slight excess of the compound of Formula vi or vii over and above this ratio is often desirable. Preferably the reaction mixture is stirred during the course of the reaction.

It is preferable to carry out the reaction producing compounds of Formula A under anhydrous conditions and in the absence of oxygen. This can be conveniently done by carrying out the reaction under an atmosphere of inert gas, such as nitrogen, argon, helium, and the like.

Organic solvents useful in this process include hydrocarbons, hydrocarbon ethers, and tertiary amines represented by Formula vii hereinabove. Illustrative solvents include hydrocarbons such as petroleum ether, cyclohexane, Z-ethylhexane, benzene, toluene, xylene, and the like, and ethers such as diethyl ether, di-isopropyl ether, methylbutyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and the like, and tertiary amines of Formula vii hereinabove.

Where highly volatile reactants, such as HCECF, t-C H CHBrCHBrF or CHF=CC1 are employed, it is 75 preferable to form the reaction mixture at C. or below and then warm the mixture to -20 C. to 25 C. where reaction will take place.

Compounds of the formula RZNCECNRZ (Y in Formula A is NR can be produced by the reaction of a compound of the formula HXC=CFX with a compound of Formula vi. The reaction mixture is preferably formed at 80" C. or below and the reaction takes place on warming to room temperature. Where a mixture of compounds of Formula vi is employed, compounds of the formula R NCECNR are produced wherein the two R N groups are different.

Where R in Formula ii is hydrogen, the reaction of a compound of Formula ii with a compound of Formula vi first produces a compound having the formula MCE CNR While the reaction of CGH5CECCI with a mixture of Lin(CH CH and N(CH gives a mixture of The relative amounts of products in such product mixtures depend on the relative reactivities of the compounds of Formulas vi and vii. In such reactant mixtures, the compound of Formula vii is both a reactant and a solvent.

Where a compound of Formula vii is used, and the R groups are not all the same, the primary product will depend on which nitrogen-R group bond is most easily broken. It has been found, for example, that a typical order of decreasing ease of R-N bond breaking is allyl-N, benzyl-N, methyl-N, ethyl-N, and n-propyl-N. Thus, the reaction of C6H5CECC1 with yields primarily When the solvent is a hydrocarbon or hydrocarbon ether, the preferred reaction temperatures are 25 C. to 20 C., and when the solvent is a tertiary amine, higher temperatures up to C. are preferred.

There is no particular advantage to be gained in carrying out the reaction at pressures other than atmospheric pressure. However, when a sealed reaction vessel is employed, the autogeneous pressure of the reaction mixture at the reaction temperature is satisfactory.

Formation of the compound of Formula A in good yield generally takes from a few hours up to several days depending on the particular temperature, solvent and reactants.

The reaction product, a compound of Formula A, is separated from the reaction mixture by conventional methods which include separation of liquid from precipitated salts and other solids, and isolation of the desired product by evaporation of solvent, fractional distillation, and the like. Product separation is preferably carried out under an inert atmosphere.

diethyl ether LiCECN(CHa)2 LiF HN(CH LiCECN(CHa)2 (CH3)2CHOH diethyl ether E WE): (CHa)zCHOLi d F s o. to 20 0. CeHsCH=C 2LiN(CHaCH3):

diethyl ether 01 C HCECN(CHzCHa)2 LiC1+ LiF HN(CH:0H;)

80 C. to 20 C. CuHtCHECCh 2LiN(CH )z dlethyl ether CuH5ECN(CHa)2 2LiCl HN(CH3)Q l H H o H c: F ammon 80 to 200 t- I l 3 a dlethyl ether Br Br lI-C4H9CECN(CH3)1 LiF 2LiBr 2HN(CH F Cl 80 C. to 20 C. C=C 3LiN(i-C4Ht)2 diethyl ether H Cl Typical classes of compounds containing non-aromatic unsaturated sites which are useful in the process of this invention are those represented by the following formulas:

( ROICCECOOR The reaction of compounds of Formula A with compounds of Formula B in about 1:1 mole ratio produces compounds represented by the formula wherein Y and R have the meanings defined hereinabove. Illustrative compounds represented by Formula AB are the following:

CHaCuH4(iJ- l s)i N N-C-C5H5 l CHz-Cg N N-o-onlomom II The reaction of compounds of Formula A with compounds of Formula C in about a 1:2 mole ratio produces compounds represented by the formula (AC) COOR Y COOR RzN -COOR wherein Y and R have the meanings defined hereinabove. Illustrative compounds represented by Formula AC are the following:

CH3C5H4 COOCHa (CH3)2N CO0CH:

0 0 0 CgHg lJ-C4H9- C 0 0 CuHlS (CzH5)2N- C O 0 (35115 0 0 O CHzCaH; Cams C O O CHnCuH /CHCH7 -C O O CHzCuHs & do 0 CH 0 H I K, a o s C O O CzHa (CH3 2N COOCaHs (CHa)2N C OOCzH;

The reaction of compounds of Formula A with compounds of Formula D in about a 1:1 mole ratio produces compounds represented by the formula (AD) Y--?:(|)NR:

N\ /NR wherein Y and R have the meanings defined hereinabove.

Illustrative compounds represented by Formula AD are the following:

The reaction of compounds of Formula A with compounds of Formula E in about a 1:1 mole ratio produces compounds represented by the formula an N-O wherein Y and R have the meanings defined hereinabove. Illustrative compounds represented by Formula AE are the following:

N-O CHZCIIQCHQOEHAC' CN(C2H5)7 CH CHaCHzCHa The reaction of compounds of Formula A with compounds of Formula F in about a 2:1 mole ratio produces compounds represented by the formula (AF) O-N N-O l I Y Y wherein Y, R and R" have the meanings defined hereinabove. Illustrative compounds represented by Formula AF are the following:

(AG) C-NR:

Y-C- II where Y, R and R have the meanings defined hereinabove, and an R and R group on the same carbon atom can together form a divalent alkylene group. Illustrative compounds represented by the Formula AG are the following.

The reaction of compounds of Formula A with compounds of Formula H in about a 1:1 mole ratio produces compounds represented b the formula (AH) Y o=o-NR,

wherein Y and R have the meanings defined hereinabove. Illustrative compounds represented by Formula AH are the following:

The reaction of compounds of Formula A with com pounds of Formula I in about a 1:1 mole ratio produces compounds represented by the formula (AI) YC=C-NR2 R'-(|3-N-R wherein Y, R and R have the meanings defined hereinabove. Illustrative compounds represented by Formula AI are the following:

CH5CH2CH2C:CN(C2H5)2 (CH3C5H4)20NCDH4CH3 oH3o@H4o=oN(oH2oBH5)2 CaH5C-N-C5H5 tC4H9C=CN(CH2CH2 a)2 (C2H5)2C-NC5H4CH3 (CH3)1NC=CN(CH3)2 (C5H5)2CNC|5H5 The compounds of Formula AI are stable at temperatures of 100 C. and above and can be distilled under reduced pressures. However, when treated with base at room temperature, the compounds of Formula AI rearrange easily to give compounds represented by the formula (AI-R) Y O o-NRQ R('3 NR wherein Y, R and R have the meanings defined hereinabove. Illustrative compounds represented by Formula AI-R are the following:

wherein Y, R, R and X have the meanings defined hereabove.

The reaction of compounds of Formula A with compounds of Formula I in about a 1:1 mole ratio produces compounds represented by the formula R(|3G-Y Rl T ("J-NR2 wherein Y, R and R have the meanings defined hereinabove. Illustrative compounds represented by Formula A] are the followin:

The compounds of Formula A also react according to the process of this invention with compounds represented by the formulas:

wherein R and R have the meanings defined hereinabove.

Also the compounds of Formula A can themselves react according to the process of this invention to give cyclic compounds of the formula wherein Y and R have the meanings defined hereinabove.

Also, the various Y and R groups in the compounds of Formula A can be substituted with one or more moieties which are inert to and do not interfere with the cycloaddition reaction of this invention, for example, halogens, halo-allcyl groups, alkoxy groups, aryloxy aryloxy groups, ether oxygen atoms and the like. Further, the two R groups on the same nitrogen can together form part of a heterocyclic ring including the nitrogen atom and one or more additional heteroatoms. For example, the compounds of Formula A- can have the structure (Y) CHZCHB Y C EC N O CHzCHz wherein Y has the meaning defined hereinabove.

Of course the various Y, R, R, R" and X groups can each represent the same or different moieties throughout a single molecule of compounds of Formulas A-Y and Formulas ii-vii hereinabove.

The compounds of Formulas AB, AC, AD, AE, AF, AG, AH, AI, AI-R, and AJ, and the compounds produced by the reaction of compounds of Formula A with compounds of Formulas K-W, react with hydrogen halides and are therefore useful under anhydrous conditions as hydrogen halide acceptors. For example, all of the above described compounds produced by the process of this invention can be used as hydrogen halide acceptors in the process for producing cyclopentadienyl metal compounds described in Morehouse, US. 3,071,605 issued Ian. 1, 1963. The compounds of Formula AIRQ react with strong bases such as lithium dimethylamide to give compounds of Formula AI-R.

The process of the present invention can be carried out with or without a solvent. However, use of inert organic solvent is preferred. Suitable inert solvents include hydrocarbons, and hydrocarbon ethers, for example, hydrocarbons such as petroleum ether, cyclohexane, 2- ethylhexane, benzene, toluene, xylene and the like, and ethers such as diethyl ether, di-isopropyl ether, methylbutyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and the like. Operable solvents also include inert halogenated hydrocarbons such as chlorobenzene, 'bromobenzene, and the like.

The temperature at which the process of this invention can be carried out varies depending upon the particular reactants, presence or absence of solvents, whether or not a catalyst is used, and the like, and the proper choice of temperature is illustrated by the examples hereinbelow. Usually temperatures from about C. up to about 100 C., and preferably from room temperature up to about C., are satisfactory. When a solvent is employed, the boiling point of the solvent is often a convenient elevated temperature.

There is no particular advantage to be gained in carrying out the process of this invention at pressures other than atmospheric pressure. However, when a sealed reaction vessel is employed, the autogeneous pressure of the reaction mixture at the reaction temperature is satisfactory.

Although not absolutely necessary, it is preferable to employ boron trifluoride as a catalyst for the cycloaddition reaction of the process of this invention when the reactant containing the non-aromatic unsaturated site is a compound of Formula G or Formula I. Amounts of BF conveniently used in the form of its etherate, in the amounts of from one to about 5 mole percent based on the amounts of reactant of Formula G or I have been found effective.

Since aminoacetylenes react readily with water, it is preferable to carry out the process of this invention under anhydrous conditions. This may be conveniently done by carrying out the process of this invention under an atmosphere of inert gas such as nitrogen, helium, argon, and the like.

The cycloaddition reaction of the process of this invention takes place in good yield in reaction times of from a few minutes up to several days depending on the particular temperature, solvent, presence or absence of catalyst, the particular reactants, and the like.

The products produced by the process of this invention can be separated from the reaction mixture by conventional methods including separation of liquid products from solid matter, isolation of the desired product by evaporation of solvent, fractional distillation, and the like. Several methods of product recovery are illustrated in the examples hereinbelow.

The ratio of reactants in the process of this invention is not narrowly critical. However, it is generally preferable to use reactant ratio which approximate the ratio in which the moieties derived from the various reactants appear in the reaction product, particularly where the Y or R groups of the compounds of formula A contain aliphatic unsaturation. Where, for example, an R or Y group of the aminoacetylene reactant contains a carbon-carbon triple bond, the cycloaddition reaction with the non-aromatic unsaturated site takes place preferentially at the aminoacetylene triple bond, that is at the functional unit -CECN Avoiding an excess of reactant containing the non-aromatic unsaturated site, eliminates any significant side reaction with other triple bonds in the compounds of formula A. Where the compound of formula A has a structure such as Ca sCECN CECCnHs the triple bonds are equivalent and the cyloaddition reaction of this invention takes place at both triple bonds.

In the reactants of formulas G, I and J, and in the products of formulas AG, AI, AIR, AIRQ and A], an R group and an R group on the same carbon atom can together form a divalent alkylene group.

In the compounds of formula I, the R group on the nitrogen atom and the R group on the carbon atom can together form a divalent alkylene group, such as -CH CH CH CH or other divalent group containing heteratoms, such as CH CH OCH CH The following examples further illustrate the process and compositions of this invention.

Example 1 Three millimoles of l-phenyl-Z-diethylaminoacetylene was added at room temperature to three millimoles of dimethyl acetylene dicarboxylate in 5 ml. of diethyl ether. After 2 hours, the solvent was evaporated, and the product N,N diethyl (2,3,4,5 tetracarbomethoxy) 6 phenylaniline was distilled under vacuum. The distillate (product) crystallized and was recrystallized from diethyl ether. Melting point C.

Analysis.-Calc.: C, 63.0; H, 5.95; N, 3.06. Found: C, 63.44; H, 5.82; N, 3.20.

Example 2 Example 3 A mixture of 0.011 mole (1.85 g.)

and 0.01 mole (2 .0 g.) of

e sCH= fi o t) were mixed in 5 ml. toluene. The mixture was heated at its boiling point for 30 minutes.

The solution, containing the desired product, was concentrated by evaporation of solvent under pressure pressure. The product fraction was further purified by recrystallization from petroleum ether.

The yield of product,

l Calls melting point 45 C., was 72%.

14 30 minutes on oily precipitate formed. The ether was evaporated. The residue, dissolved in chloroform, was washed with aqueous sodium chloride, then aqueous sodium acetate and dried over anhydrous sodium sulphate. The chloroform was evaporated and the residue fracl Examp e 4 tionally distilled under reduced pressure. The product Following the general procedures of Example 3 the fraction was further purified by recrystallization (twice) follqwlng addltlonfll examples of the Process of thls from petroleum ether, and was identified by elemental Ventlon were earned out as set Table An analysis, molecular weight determination, infra-red and products of Table 4 1 were id nniied by elemental ultra violet spectral analysis. The yield of product, analysls, molecular weight determination, and infra-red and violet spectral analysis.

In the fourth example of Table 4-1, the compound f-? C6H5CEN=NC6H5 was prepared in situ by treating C H5?=N-I |TCsH5 (lg H5 \CH3 with base. melting point 106-107 C., was 68%.

TABLE 4-1 Compound containing Melting Yield, Aminoacetylene unsaturated site Product point, 0. percent CaH5C CN(CHs)2 CeHsN=N N CBH5C=CN(CH3)2 180 59 N NCuH5 OBHACECN(CH3)Z CsHsCH=IfiICuH OH5C=CN(CH;)2 151 95 CaHaC]\I /O N (L/6H5 CHzCHe /CHzCHz OH3-C 5 CN /CH2 CaH5CH=1fiT-C 6H5 CHsCI7 -CN\ \OH2 144 89 01120112 0 CaHsCH 0 OHQCHQ N 36115 CeH5C CN(CH a)2 CeHsC N=NCoH5 CaHsC=CN(CH3)2 128 63 CsHsC N-CuHs cflHsczcNwmn C1H,fi-N=N N CsH5O=CN(CH;)2 143 71 o N N-CCH5 II N 0 r r-r (iC4Hq)zNC-=CN(iC4H )2 p(O=N C-)zCuH (l- C4H9)2NC CCH4C\ 0N(ic,Hr)l 144 f t N (l-CIHO)2 N(lC4H9)z Example 6 Example 6 A mixture of 0.01 mole of C6H CECN(CH and Following the general procedures of Example 5, the folseveral drops of BF -O(C H were mixed in 5 m1 anlowing additional examples of the process of this invention hydrous diethyl ether. To this mixture was added (dropwere carried out as set forth in Table 6-1. The products wise) at room temperature a solution of 0.01 mole phenof Table 6-1 were identified by elemental analysis, moylmethyl ketone in 5 ml diethyl ether. An exothermic lecular weight determination, and infra-red and ultra vioreaction took place which caused the ether to boil. After let spectral analysis.

TABLE 6-1 Compound containing Melting Yield, Aminoacetylene unsaturated site Product point, 0. percent CuH5CECN(CH3)z CtH5CHO CoH5C-CN(CH3)2 84-85 67 CoHrCECN (CH3); CHaC CH; CaHsC-C N(CH5)2 56-57 69 CHM"; ll

Compound containing Melting Yield, Aminoacetylene unsaturated site Product point, 0. percent CnH5C-ECN(CH3)2 CHzCH: CsHiC-CN(CH3): 65-66 57 :0 CHr-O O CHzCfiz CH2 CH1 CsH CECN (CH CHzCHg Golfing-4|? N(CH:;) 2 75-76 56 CH: /C=O CHr-C 0 CHQOHQ H: CH:

Hr-CH:

t-C4H CECN(OH3)2 CtHsCHO t-C4HuC-CN(CH;)

I II 70-71 75 CoHs O Example 7 ethylene glycol dimethyl ether, and about 5 drops of melting point 87-88 C., was obtained in 43% yield.

The product (7-1) was dissolved in diethyl ether and agitated with a 5% aqueous solution of sodium hydroxide. The organic phase was separated, dried and evaporated to dryness. The residue was the rearrangement product of compound (7-1) and had the structure CaHsC--CN(CH )1 CoHsC C5115 melting point 114 C.

Both products, (7-1) and (7-2), were identified by elemental analysis, molecular weight determination, and infra red and ultra 'violet spectrum analysis.

Example 8 Following the procedures and analysis methods of Example 7, C H CECN(CH and C H CH=NC H (with BF -0(C H catalyst) reacted to give (8-1) boiling point 140 C./0.3 mm. Hg. 70% yield. Treatment of compound (8-1) with aqueous NaOH gave (8-2) CoHsC-CN(CH )1 CaHs- I C4Hq H boiling point 145 C./ 0.1 mm. Hg. Example 9 About 0.01 mole of t-C H -CECN(CH and 0.01

mole of C H CH=NC H were dissolved in 5 ml. of

BF -O(C H was added to this solution. The reaction mixture was heated at about 70 C. for 18 hours. An oily precipitate which formed was discarded. The solution was evaporated to dryness and the residue fractionally distilled under reduced pressure. The product Example 10 The compound Ca 5 -GN( s):

CsHsC CH! prepared by the methods of Example 7, was treated with excess methyl iodide. The resulting product had the structure 11 manor. 1

What is claimed is:

1. The process which comprises 1) mixing together (a) an aminoacetylene represented by the formula YCECNR2 wherein R is a monovalent hydrocarbon group containing from one to about 18 carbon atoms, Y is selected from the class consisting of R groups, hydrogen and NR groups, and two R groups on the same nitrogen atom can together form an alkylene group of up to 10 carbon atoms, and (b) a compound represented by the formula RCON wherein R has the meaning defined hereinabove, and (2) maintaining said mixture at a temperature of from about 20 to about C., to produce a compound represented by the formula wherein R and Y have the meaning defined hereinabove.

17 2. The process which comprises (1) mixing together (a) an aminoacetylene represented by the formula YCECNRZ wherein R is a monovalent hydrocarbon group containing from one to about 18 carbon atoms, Y is selected from the class consisting of R groups, hydrogen and NR groups, and two R groups on the same nitrogen atom can together form an alkylene group of up to 10 carbon atoms, and (b) a compound represented by the formula RN wherein R has the meaning defined hereinabove, and (2) maintaining said mixture at a temperature of from about -20 C. to about 100 C., to produce a compound represented by the formula YCZCNR:

N NR

wherein R and Y have the meanings defined hereinabove.

3. A compound represented by the formula wherein R is a monovalent hydrocarbon group containing from one to about 18 carbon atoms, Y is selected from the class consisting of R groups, hydrogen and NR groups, and two R groups on the same nitrogen atom can together form an alkylene group of up to 10 carbon atoms.

4. A compound represented by the formula YCZCNR:

N NR

wherein R is a monovalent hydrocarbon group containing from one to about 18 carbon atoms, Y is selected from the class consisting of R groups, hydrogen and NR groups, and two R groups on the same nitrogen atom can together form an alkylene group of up to 10 carbon atoms.

5. The compound represented by the formula US. Cl. X.R. 

